DOCSLIB.ORG

Clinical Pharmacokinetic Noncompartmental Data Analysis Plan

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Clinical Pharmacokinetic Noncompartmental Data Analysis Plan CLINICAL RESEARCH IN INFECTIOUS DISEASES Clinical Pharmacokinetic Noncompartmental Data Analysis Plan For DMID Protocol: 16-0118 Study Title: A Phase 1 Clinical Trial to Evaluate the Plasma Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of Zoliflodacin in Healthy Male and Female Subjects Version 1.0 DATE: 03 April 2018 Prepared and Distributed by: The Emmes Corporation Rockville, Maryland USA THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL - i - PRIVILEGED AND CONFIDENTIAL COMMUNICATION The Emmes Corporation Version 1.0 Noncompartmental Pharmacokinetic Analysis Plan – DMID Protocol: 16-0118 03 April 2018 TABLE OF CONTENTS ACRONYMS AND ABBREVIATIONS ......................................................................................III 1. PREFACE .....................................................................................................................1 2. CLINICAL STUDY METHODS ..............................................................................2 2.1. Analysis Groups ............................................................................................................2 2.2. Dose Administration .....................................................................................................2 2.3. PK Sampling Schedule .................................................................................................2 2.4. Analytical Methods .......................................................................................................2 2.5. Collection of Pharmacodynamic or Clinical Endpoints ...............................................2 3. PHARMACOKINETIC ANALYSIS METHODS ..................................................3 3.1. Analysis Population and Handling of Missing Time Points .........................................3 3.2. Demographic and Baseline Characteristics ..................................................................3 3.3. Dosing and Pharmacokinetic Sampling Summary .......................................................3 3.4. Definition and Estimation of Individual NCA PK Parameters .....................................4 3.5. Descriptive Statistics ....................................................................................................6 3.6. Reporting Conventions .................................................................................................6 4. REFERENCES .............................................................................................................7 5. LISTING OF PROPOSED TABLES, FIGURES, AND LISTINGS ...........................8 6. APPENDICES ..............................................................................................................9 APPENDIX 1. LIST OF PROPOSED PK TABLES ..................................................................10 APPENDIX 2. LIST OF PROPOSED PK FIGURES ................................................................14 APPENDIX 3. LIST OF PROPOSED PK LISTINGS ...............................................................19 - ii - PRIVILEGED AND CONFIDENTIAL COMMUNICATION The Emmes Corporation Version 1.0 Noncompartmental Pharmacokinetic Analysis Plan – DMID Protocol: 16-0118 03 April 2018 ACRONYMS AND ABBREVIATIONS Standard acronyms and abbreviations are listed below. Abbreviation Definition AUC Area Under the Concentration-Time Curve AUC(0-last) AUC to the Last Measurable Concentration AUC(0-t) AUC from 0 to time t AUC(0-∞) AUC Extrapolated to Infinity BMI Body Mass Index BQL Below the Quantification Limit Clast Last Measurable Concentration (above the quantification limit) CL/F Apparent Oral Clearance cm Centimeter(s) Cmax Maximum Plasma Concentration CSR Clinical Study Report CV Coefficient of Variation EDC Electronic Data Capture g Gram(s) GM Geometric Mean GSD Geometric Standard Deviation h Hour(s) HPLC- High-Performance Liquid Chromatography with Tandem Mass MS/MS Spectrometry Ke Terminal Phase Elimination Rate Constant kg Kilogram(s) L Liter(s) LLOQ Lower Limit of Quantification Max Maximum Min Minimum min Minute(s) mL Milliliter(s) NCA Noncompartmental Analysis ng Nanogram(s) PK Pharmacokinetic(s) SD Standard Deviation t1/2 Apparent Terminal Elimination Half-Life Tlast Time of Last Measurable Concentration Tmax Time to Maximum Plasma Concentration (Cmax) Vz/F Apparent Volume of Distribution During Terminal Phase - iii - PRIVILEGED AND CONFIDENTIAL COMMUNICATION The Emmes Corporation Version 1.0 Noncompartmental Pharmacokinetic Analysis Plan – DMID Protocol: 16-0118 03 April 2018 1. PREFACE DMID protocol 16-0118 is a Phase 1 study of zoliflodacin in healthy male and female subjects. The pharmacokinetics (PK)-related objectives of the study are: • To evaluate the plasma PK of zoliflodacin after administration of a single 4 g oral dose under fasting conditions This document reiterates key PK elements in the study design of DMID Protocol 16-0118 and thoroughly describes the presentations and summaries of PK data as well as the noncompartmental analysis (NCA) to be included in the PK Report and summarized in the clinical study report (CSR) for this protocol. Shells and mockups are given for all PK-related tables, figures, and listings planned for inclusion in the CSR and/or PK Report. At minimum, mean PK plots as well as listings and summaries of zoliflodacin concentrations and PK parameters will be included in the CSR, while all tables, figures, and listings described in this document will be included in the PK Report. - 1 - PRIVILEGED AND CONFIDENTIAL COMMUNICATION The Emmes Corporation Version 1.0 Noncompartmental Pharmacokinetic Analysis Plan – DMID Protocol: 16-0118 03 April 2018 2. CLINICAL STUDY METHODS 2.1. Analysis Groups This is a Phase 1, open-label clinical trial of a single 4 g oral dose of zoliflodacin after an overnight fast. Eight healthy subjects who consent to participate in the trial and meet the eligibility criteria will be enrolled into a single cohort. Stratification will not be used in this study. All subjects will be analyzed in a single analysis group and no comparisons will be performed. 2.2. Dose Administration Eligible subjects will receive a single 4 g dose (2 sachets of 2 g of zoliflodacin reconstituted on the same day and administered in a total of ) orally after an overnight fast. The dose will be administered in a standardized cup. After the of zoliflodacin is administered, an additional will be added to the same cup and consumed by the subject to chase the initial dose. Both doses will be completed within a total of 5 min. After dosing, subjects will continue to fast for an additional 4 h while water is allowed ad lib. 2.3. PK Sampling Schedule Blood (plasma) samples will be collected into K2EDTA tubes at the following time points: On Day 1 at 30 min before dosing, and 0.5 h (±5 min), 1 h (±5 min), 2 h (±5 min), 3 h (±10 min), 4 h (±10 min), 6 h (±10 min), 8 h (±15 min), and 12 h (±15 min) after dosing; on Day 2 at 24 h (± 2 h) and 36 h (± 2 h) after dosing; on Day 3 at 48 h (±2 h) after dosing; and on Day 4 at 72 h (±2 h) after dosing, or early termination. 2.4. Analytical Methods Plasma concentrations of zoliflodacin will be determined using a validated HPLC-MS/MS method. The analysis will be performed by KCAS Bioanalytical Services. Details are included in the assay validation. For details of sample collection, processing, storage, transportation, and bioanalysis, see the protocol, MOP, and assay validation documents. 2.5. Collection of Pharmacodynamic or Clinical Endpoints Not applicable. - 2 - PRIVILEGED AND CONFIDENTIAL COMMUNICATION The Emmes Corporation Version 1.0 Noncompartmental Pharmacokinetic Analysis Plan – DMID Protocol: 16-0118 03 April 2018 3. PHARMACOKINETIC ANALYSIS METHODS 3.1. Analysis Population and Handling of Missing Time Points All subjects who received the study drug and who have at least one measurable drug concentration post- dosing will be included in the PK analysis population. Additionally, there will be a PK analysis subset, which includes all subjects who completed the PK part of the trial without any protocol violations or deviations that would likely affect the PK results and who have evaluable plasma concentration data for zoliflodacin from which at least the Cmax and Tmax can be determined (peak concentration and at least one decreased concentration after the peak observed). Zoliflodacin concentrations will be listed and shown graphically as individual profiles for all subjects in the PK analysis population, but concentration summary statistics, mean PK profiles, and NCA will use the PK analysis subset only. All enrolled subjects excluded from the PK analysis population or the PK analysis subset will be described in the PK Report, including reason for exclusion. Collection of plasma samples outside of the protocol defined time window for the time point will not result in exclusion of the sample result from NCA. If a sample is collected more than 10 min outside of the protocol defined time window, the sample result will be excluded from calculation of summary statistics for the respective time point, as well as from plots of mean concentration. Values below the lower limit of quantification (LLOQ) will be referred to as below the quantification limit (BQL). BQL values that precede the first PK concentration above the LLOQ will be imputed as 0 for linear plots and for all calculations including NCA and summary statistics, but will be excluded from semi- logarithmic plots. All other BQL values will be treated as missing for all analyses. Missing pre-dose PK samples will have concentrations
Load more

Recommended publications
  • Overcoming Fluoroquinolone Resistance: Mechanistic Basis of Non- Quinolone Antibacterials Targeting Type Ii Topoisomerases
    OVERCOMING FLUOROQUINOLONE RESISTANCE: MECHANISTIC BASIS OF NON- QUINOLONE ANTIBACTERIALS TARGETING TYPE II TOPOISOMERASES By Elizabeth Grace Gibson Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmacology May 10, 2019 Nashville, Tennessee Approved: Neil Osheroff, Ph.D. Joey Barnett, Ph.D. Wendell S. Akers, Pharm.D., Ph.D. Sean Davies, Ph.D. Benjamin Spiller, Ph.D. Timothy R. Sterling, M.D. DEDICATION To all my family and church family who have supported and encouraged me over all my years in school. To Him who I put all my trust. Commit your way to the Lord, trust also in Him and He shall bring it to pass. Psalm 37:5 ii ACKNOWLEDGEMENTS I want to first thank my Ph.D. advisor, Dr. Neil Osheroff, for allowing me to work in his laboratory. Thank you for all your support and encouragement and just being an overall great mentor. You really know how to bring us up when we need it or give us an ego check when we get a little high and mighty when things are going well. I appreciate your supportiveness to careers outside academia. I also appreciate that you always have our best interest at heart. To Dr. Joe Deweese, my first research mentor and the one who instilled the love of topoisomerase research. Without your guidance I would not be where I am today. Thank you for introducing me to Neil and his laboratory and helping with the transition from research in your lab to his.
    [Show full text]
  • Target Product Profiles for Needed Antibacterial Agents
    TARGET PRODUCT PROFILES FOR NEEDED ANTIBACTERIAL AGENTS: enteric fever, gonorrhoea, neonatal sepsis, urinary tract infections and meeting report TARGET PRODUCT PROFILES FOR NEEDED ANTIBACTERIAL AGENTS: enteric fever, gonorrhoea, neonatal sepsis, urinary tract infections and meeting report TARGET PRODUCT PROFILES FOR NEEDED ANTIBACTERIAL AGENTS: enteric fever, gonorrhoea, neonatal sepsis, urinary tract infections and meeting report Target product profiles for needed antibacterial agents: enteric fever, gonorrhoea, neonatal sepsis, urinary tract infections and meeting report ISBN 978-92-4-000389-7 (electronic version) ISBN 978-92-4-000390-3 (print version) © World Health Organization 2020 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/ by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization.
    [Show full text]
  • 2020 Antibacterial Agents in Clinical and Preclinical
    2020 ANTIBACTERIAL AGENTS IN CLINICAL AND PRECLINICAL DEVELOPMENT an overview and analysis 2020 ANTIBACTERIAL AGENTS IN CLINICAL AND PRECLINICAL DEVELOPMENT an overview and analysis 2020 ANTIBACTERIAL AGENTS IN CLINICAL AND PRECLINICAL DEVELOPMENT an overview and analysis 2020 Antibacterial agents in clinical and preclinical development: an overview and analysis ISBN 978-92-4-002130-3 (electronic version) ISBN 978-92-4-002131-0 (print version) © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization (http://www.wipo.int/amc/en/mediation/rules/).
    [Show full text]
  • Antibiotics in the Clinical Pipeline in October 2019
    The Journal of Antibiotics (2020) 73:329–364 https://doi.org/10.1038/s41429-020-0291-8 REVIEW ARTICLE Antibiotics in the clinical pipeline in October 2019 1 1 Mark S. Butler ● David L. Paterson Received: 17 December 2019 / Revised: 30 January 2020 / Accepted: 30 January 2020 / Published online: 10 March 2020 © The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2020 Abstract The development of new and effective antibacterial drugs to treat multi-drug resistant (MDR) bacteria, especially Gram- negative (G−ve) pathogens, is acknowledged as one of the world’s most pressing health issues; however, the discovery and development of new, nontoxic antibacterials is not a straightforward scientific task, which is compounded by a challenging economic model. This review lists the antibacterials, β-lactamase/β-lactam inhibitor (BLI) combinations, and monoclonal antibodies (mAbs) first launched around the world since 2009 and details the seven new antibiotics and two new β-lactam/ BLI combinations launched since 2016. The development status, mode of action, spectra of activity, lead source, and administration route for the 44 small molecule antibacterials, eight β-lactamase/BLI combinations, and one antibody drug conjugate (ADC) being evaluated in worldwide clinical trials at the end of October 2019 are described. Compounds discontinued from clinical development since 2016 and new antibacterial pharmacophores are also reviewed. There has been 1234567890();,: 1234567890();,: an increase in the number of early stage clinical candidates, which has been fueled by antibiotic-focused funding agencies; however, there is still a significant gap in the pipeline for the development of new antibacterials with activity against β-metallolactamases, orally administered with broad spectrum G−ve activity, and new treatments for MDR Acinetobacter and gonorrhea.
    [Show full text]
  • New Antibiotics for Multidrug-Resistant Bacterial Strains: Latest Research Developments and Future Perspectives
    molecules Review New Antibiotics for Multidrug-Resistant Bacterial Strains: Latest Research Developments and Future Perspectives Marco Terreni, Marina Taccani and Massimo Pregnolato * Department of Drug Science, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy; [email protected] (M.T.); [email protected] (M.T.) * Correspondence: [email protected]; Tel.: +39-0382-987583 Abstract: The present work aims to examine the worrying problem of antibiotic resistance and the emergence of multidrug-resistant bacterial strains, which have now become really common in hospitals and risk hindering the global control of infectious diseases. After a careful examination of these phenomena and multiple mechanisms that make certain bacteria resistant to specific antibiotics that were originally effective in the treatment of infections caused by the same pathogens, possible strategies to stem antibiotic resistance are analyzed. This paper, therefore, focuses on the most promising new chemical compounds in the current pipeline active against multidrug-resistant organisms that are innovative compared to traditional antibiotics: Firstly, the main antibacterial agents in clinical development (Phase III) from 2017 to 2020 are listed (with special attention on the treatment of infections caused by the pathogens Neisseria gonorrhoeae, including multidrug-resistant isolates, and Clostridium difficile), and then the paper moves on to the new agents of pharmacological interest that have been approved during the same period. They include tetracycline derivatives (eravacycline), fourth generation fluoroquinolones (delafloxacin), new combinations between one β-lactam and one β-lactamase inhibitor (meropenem and vaborbactam), siderophore cephalosporins Citation: Terreni, M.; Taccani, M.; (cefiderocol), new aminoglycosides (plazomicin), and agents in development for treating drug- Pregnolato, M.
    [Show full text]
  • Request for Proposal
    Request For Proposal A Phase 1, Open-Label, Study to Investigate Pharmacokinetics, Effect of Food and Safety of a New Immediate-Release Formulation of Zoliflodacin and Optional Single Dose Study to Assess Pharmacokinetics, Safety and Tolerability of Zoliflodacin in Healthy Subjects Dated: May 15th 2018 Zoliflodacin Food Effects and Optional Single Dose-Escalation in Healthy Male and Female Subjects RFP Page 1 of 14 Table of Contents 1 PURPOSE .......................................................................................................................3 2 RFP INSTRUCTIONS ....................................................................................................3 2.1 General information .................................................................................................3 2.2 Timelines .................................................................................................................4 2.3 RFP processes and contact information ....................................................................5 2.3.1 Instructions........................................................................................................5 2.3.2 Confirmation of Intent .......................................................................................5 2.4 Format and content of the proposal ...........................................................................6 3 GARDP STI PROGRAM OVERVIEW ...........................................................................7 4 SCOPE OF WORK .........................................................................................................7
    [Show full text]
  • Drug-Resistant Gonorrhea and Other Emerging Issues in Stis Sexually Transmitted Infections Are Increasing in the United States
    NEWS & BREAKTHROUGHS 4.18 | V. 3 | N. 2 The Shingrix Vaccine: What You Should Know CONTAGIONLIVE.COM By Jennifer Gershman, PharmD, CPh (continued on page 10) Infectious Diseases Today 2018 BMT Tandem CROI 2018 Meetings D/C/F/TAF Performs Considerations for Well in Treatment- CMV in Allogeneic Experienced Patients HSCT Recipients lthough significant advances wo poster presentations at the have been made in the treat- 2018 BMT Tandem Meetings of ment of HIV, certain patient the Center for International populationsA continue to face barriers TBlood & Marrow Transplant Research to viral suppression. Treatment-ex- and the American Society for Blood and perienced patients from diverse Marrow Transplantation held in Salt backgrounds who may have strug- City, Utah, provided a gled with adherence in the past are compelling extension facing the issue of drug resistance. of the recent phase Therefore, new treat- 3 clinical trial1 that de- ment options for monstrated the effi- these patients need cacy of prophylactic © Juergen Berger/ Science Source to be developed and therapy with leter- made available. The Roy F Chemaly, MD, MPH, FACP, FIDSA movir (Prevymis) for 48-week results of a the prevention of cytomegalovirus Neisseria gonorrhoeae post hoc analysis of (CMV) infection in patients receiving Gregory D. Huhn, MD clinical trial testing allogeneic hematopoietic stem cell trans- EMERGING & RE-EMERGING DISEASES of one of these new agents in treat- plantation (HSCT). ment-experienced patients—the Immunosuppression is necessary Drug-Resistant Gonorrhea and EMERALD trial—were recently pre- for the success of HSCT, but it carries sented at the 25th Annual Confer- the danger of lessened resistance to Other Emerging Issues in STIs ence on Retroviruses and Opportu- potentially lethal infections like CMV, By Nicola M.
    [Show full text]
  • Developing a New Drug for Sexually Transmitted Infections
    Developing a new drug for Sexually Transmitted Infections Emilie Alirol, PhD Antimicrobial Chemotherapy Conference, 15 January 2019 Royal College of Physicians, London Content • Global burden of Sexually Transmitted Infections • GARDP Research & Development strategy for STIs • Zoliflodacin project • Project timelines and partners Global burden of STIs 357 million new cases every year STI manifestation and complications • Gonorrhea: 78 million cases Pelvic inflammatory disease (PID); Chronic pelvic pain; • Chlamydia: 131 million cases Ectopic pregnancy; Spontaneous abortions and • Trichomonas: 143 million cases Stillbirth; Post-partum infections; Infertility; neonatal • Syphilis: 5.6 million cases conjunctivitis and blindness; increase HIV transmission Infections due to Neisseria gonorrhoeae • LeadinG cause of urethral discharche worldwide • HiGhest prevalence and incidence in Western Pacific, Africa and South East Asia • Infections in women mainly asymptomatic • IndistiGuishable from Chlamydia or Mycoplasma infections • Remarkable capacity to acquire resistance; Listed as a priority pathogen in AMR lists by WHO, US, Canada and UK Spread of gonococcal resistance • All antibiotics used since the 30s have elicited resistance • Resistance to ESC and azithromycin is on the rise; Multi-drug resistant strains are circulating globally; a few treatment failures linked to these strains have been reported. • Neisseria gonorrhoeae is listed in several priority pathogens list (e.g. WHO, US CDC, Canada) Azithromycin Extended Spectrum Cephalosporin (ESC)
    [Show full text]
  • 1 Development Considerations of Antimicrobial Drugs for 1 The
    1 1 Development Considerations of Antimicrobial Drugs for 2 the Treatment of Gonorrhea 3 4 5 Friday, April 23, 2021 6 9:00 a.m. 7 8 9 Remote Proceeding 10 Washington, D.C. 20001 11 12 13 14 15 16 17 18 Reported by: Carl Hellandsjo 19 JOB No.: 4500552 20 21 22 A P P E A R A N C E S 2 1 Lindley Barbee, University of Washington, 2 Radu Botgros, EMA, 3 Juan Bravo, Debiopharm International SA, 4 Sue Cammarata, Tunnell Government Services, 5 Ricardo Chaves, Debiopharm International SA, 6 Guennaelle Dieppois, Debiopharm International SA, 7 George Drusano, University of Florida, 8 Erin Duffy, CARB-X, 9 Scott Evans, George Washington University, 10 Helen Fifer, Public Health England, 11 Steve Gelone, Nabriva Therapeutics, 12 Khalil Ghanem, Johns Hopkins University, 13 Matthew Golden, University of Washington, 14 Edward Hook, University of Alabama-Birmingham, 15 Ann Jerse, Uniformed Services University, 16 Jeff Klausner, USC, 17 Jeanne Marrazzo, University of Alabama-Birmingham, 18 Candice McNeil, Wake Forest University Health 19 Sciences, 20 Seamus O’Brien, GARDP, 21 Caroline Perry, GlaxoSmithKline, 22 A P P E A R A N C E S (Cont'd) 3 1 Hilary Reno, Washington University, 2 Nicole Scangarella-Oman, GlaxoSmithKline, 3 Olusegun Soge, University of Washington, 4 Magnus Unemo, Orebro University, 5 Brian VanScoy, Institute for Clinical 6 Pharmacodynamics, 7 Teodora Elvira Wi, WHO, 8 Kimberly Workowski, Emory University, 9 Jonathan Zenilman, Johns Hopkins University 10 Laura Bachman, CDC, 11 Kyle Bernstein, CDC, 12 Carolyn Deal, NIAID, 13 Ann Eakin,
    [Show full text]